The family of mammalian protease-activated receptors (PARs), belonging to G protein-coupled receptor (GPCR) is composed of four genes. PAR1 is activated following the release of N-terminal peptide and the exposure of an otherwise hindered ligand. This exclusive mode of activation serves as a general paradigm for the entire PAR family. Expression of hPar1 and epithelial tumor progression are directly correlated in both clinically obtained biopsy specimens and a wide spectrum of differentially metastatic cell lines (Even-Ram S, et al. (1998) Nat Med 4: 909-914). PAR1 has been shown to play a central role in the invasive and metastatic cancers of breast, ovaries, lung, colon, prostate and melanoma (Grisaru-Granovsky S, et al. (2005) Int J Cancer 113: 372-378; Nierodzik M L, et al (1998) Blood 92(10):3694-700; Salah Z, et al (2005) FASEB J 19(1):62-72; Granovsky-Grisaru S, et al (2006) Gynecol Oncol 103(3):802-6; Agarwal A, et al (2008) Mol Cancer Ther 7(9):2746-57).
Importantly, PAR1 cellular trafficking and signal termination appear to occur in a different mode than other GPCRs. Instead of recycling back to the cell surface after ligand stimulation, activated PAR1 is sorted to the lysosomes and degraded. Aberrant PAR1 trafficking, resulting in receptor-populated cell surfaces and causing prolonged and persistent signals, has been found in breast cancer (Booden M A, et al (2004) Mol Cell Biol. 24:1990-1999). While cellular trafficking of PAR1 impinges on the extent and mode of signaling, identification of individual PAR1 signaling partners and their contribution to breast cancer progression remain yet to be elucidated.
Surprisingly, PAR2, the second member which is not considered a thrombin-receptor (in contrast to PAR1, 3 and 4) was found to be connected to coagulation by virtue of its activation by other coagulation proteases such as tissue factor; TF bound to FVIIa (factor VIIa); TF-FVIIa. PAR2 was associated with promotion of breast cancer (Su S, et al (2009) Oncogene 28(34):3047-57).